Though many transgenic models of Alzheimer's disease (AD) have been created, to date no model has convincingly captured the neuronal cell death aspect of AD. There is accumulating evidence that neuronal cell death in AD is the result of AD-related protein destabilization of intracellular calcium homeostasis. It has also been found that susceptibility to excitotoxin-induced cell death (which ultimately disrupts intracellular calcium homeostasis) varies between mouse strains and most of the current transgenic models have been created on excitotoxin-resistant strains. The following proposal aims to investigate the effect of mouse background strain on beta amyloid aggregation, tau accumulation, and neuronal cell death in a triple transgenic mouse model of AD (3xTg-AD) that develops both beta amyloid plaques and neurofbrilary tangles. This study will be approached through continuous breeding of the 3xTg-AD mouse onto a mouse strain that is susceptible to excitotoxic injury. Extensive histological and biochemical evaluation and stereological analysis will then be done to determine if sensitivity to excitotoxic insult affects AD pathology- induced neuronal cell loss. There is still much debate over the ultimate cause of Alzheimer disease. Before we can effectively study possible treatments for AD in a mouse, it may be essential to develop a model that encompasses the major pathological hallmarks, including vast neuronal cell loss. Not only could this project generate a more accurate model of AD, but would also serve to support the calcium dyshomeostasis theory of AD pathogenesis and could potentially lead to more effective therapeutic treatments for those who suffer from, or risk developing, Alzheimer's disease.